Abstract
Cells infected with dengue virus release a high proportion of immature prM-containing virions. In accordance, substantial levels of prM antibodies are found in sera of infected humans. Furthermore, it has been recently described that the rates of prM antibody responses are significantly higher in patients with secondary infection compared to those with primary infection. This suggests that immature dengue virus may play a role in disease pathogenesis. Interestingly, however, numerous functional studies have revealed that immature particles lack the ability to infect cells. In this report, we show that fully immature dengue particles become highly infectious upon interaction with prM antibodies. We demonstrate that prM antibodies facilitate efficient binding and cell entry of immature particles into Fc-receptor-expressing cells. In addition, enzymatic activity of furin is critical to render the internalized immature virus infectious. Together, these data suggest that during a secondary infection or primary infection of infants born to dengue-immune mothers, immature particles have the potential to be highly infectious and hence may contribute to the development of severe disease.
Highlights
Dengue virus (DENV) represents a major emerging arthropodborne pathogen
Each of the four circulating serotypes can cause disease ranging from febrile illness to devastating manifestations including dengue hemorrhagic fever and dengue shock syndrome
Severe illness is observed in individuals experiencing a reinfection with a heterologous dengue virus serotype and in infants born to dengue-immune mothers, presumably due to antibody-dependent enhancement of infection
Summary
Dengue virus (DENV) represents a major emerging arthropodborne pathogen. There are four distinct serotypes of DENV which, according to WHO estimates, infect about 50-100 million individuals annually, mostly in the (sub)tropical regions of the world. While most DENV infections are asymptomatic or result in self-limited dengue fever (DF), an increasing number of patients present more severe, potentially fatal clinical manifestations, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). It is well established that a major risk factor for the development of DHF/DSS is secondary infection with a heterotypic virus serotype [1,2,3]. Primary infection of infants born to dengue-immune mothers may lead to severe disease [1,4,5]. These observations have led to the hypothesis of antibody-dependent enhancement (ADE) of infection [3,6,7]. The molecular mechanisms by which antibodies enhance DENV infection remain elusive
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